Training, detraining, and retraining: Two 12-week respiratory muscle training regimens in a child with infantile-onset Pompe disease.

BACKGROUND: Respiratory muscle weakness is a primary cause of morbidity and mortality in patients with Pompe disease. We previously described the effects of our 12-week respiratory muscle training (RMT) regimen in 8 adults with late-onset Pompe disease [1] and 2 children with infantile-onset Pompe disease [2]. CASE REPORT: Here we describe repeat enrollment by one of the pediatric participants who completed a second 12-week RMT regimen after 7 months of detraining. We investigated the effects of two 12-week RMT regimens (RMT #1, RMT #2) using a single-participant A-B-A experimental design. Primary outcome measures were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function. RELEVANCE: From pretest to posttest, RMT #2 was associated with a 25% increase in MIP and a 22% increase in MEP, corresponding with very large effect sizes (d= 2.92 and d= 2.65, respectively). Following two 12-week RMT regimens over 16 months, MIP increased by 69% and MEP increased by 97%, corresponding with very large effect sizes (d= 3.57 and d= 5.10, respectively). MIP and MEP were largely stable over 7 months of detraining between regimens. Magnitude of change was greater for RMT #1 relative to RMT #2.

Rehabilitation Management of the Patient With Duchenne Muscular Dystrophy.

Steadily improving management of Duchenne muscular dystrophy (DMD) continues to lead to improved physical and functional status, allowing increasingly successful transitions to independence and self-actualization in adulthood. Rehabilitation principles remain key to overall management for individuals with DMD with increasing options for ever more successful management, reflecting a changing natural history based on the use of glucocorticoids, more consistent comprehensive care, and the emergence of disease-modifying treatments. Advances and expansion in assessment, cardiorespiratory management, preventive management of contracture and deformity, assistive technology, "smart" technology, and robotics with increased emphasis on function, participation, self-advocacy, and independence in decision-making should allow individuals with DMD to experience childhood and transition to adulthood with support that allows for increasing success in the achievement of individual goals and fulfillment across the life span.

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management.

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.

Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): Effects of training and detraining.

BACKGROUND: Determine the effects of a 12-week respiratory muscle training (RMT) program in late-onset Pompe disease (LOPD). METHODS: We investigated the effects of 12-weeks of RMT followed by 3-months detraining using a single-subject A-B-A experimental design replicated across 8 adults with LOPD. To assess maximal volitional respiratory strength, our primary outcomes were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function, and peak cough flow (PCF) was measured in the last 5 subjects. RESULTS: From pretest to posttest, all 8 subjects exhibited increases in MIP, and 7 of 8 showed increases in MEP. Effect size data reveal the magnitude of increases in MIP to be large in 4 (d≥1.0) and very large in 4 (d≥2.0), and effect sizes for increases in MEP were large in 1 (d≥1.0) and very large in 6 (d≥2.0). Across participants, pretest to posttest MIP and MEP increased by a mean of 19.6% (sd=9.9) and 16.1% (sd=17.3), respectively. Respiratory strength increases, particularly for the inspiratory muscles, were generally durable to 3-months detraining. CONCLUSIONS: These data suggest our 12-week RMT program results in large to very large increases in inspiratory and expiratory muscle strength in adults with LOPD. Additionally, increases in respiratory strength appeared to be relatively durable following 3-months detraining. Although additional research is needed, RMT appears to offer promise as an adjunctive treatment for respiratory weakness in LOPD.

Exome sequencing results in successful riboflavin treatment of a rapidly progressive neurological condition.

Genetically targeted therapies for rare Mendelian conditions are improving patient outcomes. Here, we present the case of a 20-mo-old female suffering from a rapidly progressing neurological disorder. Although diagnosed initially with a possible autoimmune condition, analysis of the child's exome resulted in a diagnosis of Brown-Vialetto-Van Laere syndrome 2 (BVVLS2). This new diagnosis led to a change in the therapy plan from steroids and precautionary chemotherapy to high-dose riboflavin. Improvements were reported quickly, including in motor strength after 1 mo. In this case, the correct diagnosis and appropriate treatment would have been unlikely in the absence of exome sequencing and careful interpretation. This experience adds to a growing list of examples that emphasize the importance of early genome-wide diagnostics.

Sustained therapeutic response to riboflavin in a child with a progressive neurological condition, diagnosed by whole-exome sequencing.

One of the most promising outcomes of whole-exome sequencing (WES) is the alteration of medical management following an accurate diagnosis in patients with previously unresolved disorders. Although case reports of targeted therapies resulting from WES have been published, there are few reports with long-term follow-up that confirm a sustained therapeutic response. Following a diagnosis by WES of Brown-Vialetto-Van Laere Syndrome 2 (BVVLS2), high-dose riboflavin therapy was instituted in a 20-mo-old child. An immediate clinical response with stabilization of signs and symptoms was noted over the first 2-4 wk. Subsequent clinical follow-up over the following 8 mo demonstrates not just stabilization, but continuing and sustained improvements in all manifestations of this usually fatal condition, which generally includes worsening motor weakness, sensory ataxia, hearing, and vision impairments. This case emphasizes that early application of WES can transform patient care, enabling therapy that in addition to being lifesaving can sometimes reverse the disabling disease processes in a progressive condition.

Effects of respiratory muscle training (RMT) in children with infantile-onset Pompe disease and respiratory muscle weakness.

PURPOSE: Respiratory muscle weakness is a primary therapeutic challenge for patients with infantile Pompe disease. We previously described the clinical implementation of a respiratory muscle training (RMT) regimen in two adults with late-onset Pompe disease; both demonstrated marked increases in inspiratory and expiratory muscle strength in response to RMT. However, the use of RMT in pediatric survivors of infantile Pompe disease has not been previously reported. METHOD: We report the effects of an intensive RMT program on maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) using A-B-A (baseline-treatment-posttest) single subject experimental design in two pediatric survivors of infantile Pompe disease. Both subjects had persistent respiratory muscle weakness despite long-term treatment with alglucosidase alfa. RESULTS: Subject 1 demonstrated negligible to modest increases in MIP/MEP (6% increase in MIP, d=0.25; 19% increase in MEP, d=0.87), while Subject 2 demonstrated very large increases in MIP/MEP (45% increase in MIP, d=2.38; 81% increase in MEP, d=4.31). Following three-month RMT withdrawal, both subjects maintained these strength increases and demonstrated maximal MIP and MEP values at follow-up. CONCLUSION: Intensive RMT may be a beneficial treatment for respiratory muscle weakness in pediatric survivors of infantile Pompe disease.

Improvement with ongoing Enzyme Replacement Therapy in advanced late-onset Pompe disease: a case study.

Benefits of enzyme replacement therapy with Myozyme (alglucosidase alfa), anecdotally reported in late-onset Pompe disease, range from motor and pulmonary improvement in less severely affected patients, to stabilization with minimal improvement in those with advanced disease. We report a case of a 63-year-old patient with significant morbidity who made notable motor and pulmonary function gains after two years on therapy. Thus, improvements in those with advanced disease may be possible after long-term treatment.